A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy

Chai, Qiyao; Wang, Xudong; Qiang, Lihua; Zhang, Yong; Ge, Pupu; Lü, Zhe; Zhong, Yanzhao; Li, Bingxi; Wang, Jing; Zhang, Lingqiang; Zhou, Dawang; Li, Wei; Dong, Wenzhu; Pang, Yu; Gao, George F.; Liu, Cui Hua

doi:10.1038/s41467-019-09955-8

Cited by 125 publications

(95 citation statements)

References 69 publications

(129 reference statements)

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“…Finally, since Mtb is an exquisitely evolved pathogen, it is very likely that yet-to-be-identified bacterial proteins are intimately involved in these processes. Indeed, the recent discovery of a ubiquitin-binding protein (Rv1468c) on Mtb's surface suggests that Mtb does have mechanisms for modulating the host's selective autophagy pathway (Chai et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to controlMycobacterium tuberculosisinfection in macrophages

Bell

Lopez

Cox³

et al. 2020

Preprint

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ABSTRACTMycobacterium tuberculosis (Mtb) infects a quarter of the world and causes the deadliest infectious disease worldwide. Upon infection, Mtb is phagocytosed by macrophages and uses its virulence-associated ESX-1 secretion system to modulate the host cell and establish a replicative niche. We have previously shown the ESX-1 secretion system permeabilizes the Mtb-containing phagosome and that a population (~30%) of intracellular Mtb are recognized within the cytosol, tagged with ubiquitin, and targeted to the selective autophagy pathway. Despite the importance of selective autophagy in controlling infection, the mechanisms through which macrophages sense and respond to damaged Mtb-containing phagosomes remains unclear. Here, we demonstrate that several cytosolic glycan-binding proteins, known as galectins, recognize Mtb-containing phagosomes. We found that galectins-3, -8, and -9 are all recruited to the same Mtb population that colocalizes with selective autophagy markers like ubiquitin, p62, and LC3, which indicates Mtb damages its phagosomal membrane such that cytosolic host sensors can recognize danger signals in the lumen. To determine which galectins are required for controlling Mtb replication in macrophages, we generated CRISPR/Cas9 knockout macrophages lacking individual or multiple galectins and found that galectin-8-/- and galectin-3/8/9-/- knockout macrophages were similarly defective in targeting Mtb to selective autophagy and controlling replication, suggesting galectin-8 plays a privileged role in anti-Mtb autophagy. In investigating this specificity, we identified a novel and specific interaction between galectin-8 and TAX1BP1, one of several autophagy adaptors that bridges cargo and LC3 during the course of autophagosome formation, and this galectin-8/TAX1BP1 interaction was necessary to efficiently target Mtb to selective autophagy. Remarkably, overexpressing individual galectins increased targeting of Mtb to antibacterial autophagy and limited Mtb replication. Taken together, these data imply that galectins recognize damaged Mtb-containing phagosomes, recruit downstream autophagy machinery, and may represent promising targets for host-directed therapeutics to treat Mtb.

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Section: Discussionmentioning

confidence: 99%

Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to controlMycobacterium tuberculosisinfection in macrophages

Bell

Lopez

Cox³

et al. 2020

Preprint

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“…P62 and NDP52 are two classic receptors implicated in xenophagy. P62 assembles on the microbes as receptors once the cells were affected by pathogens, such as Salmonella [142] and mycobacteria [143]. NDP52 can be recruited as xenophagy receptors for Salmonella [144].…”

Section: Autophagy Receptors In Macrophagementioning

confidence: 99%

Autophagy and Macrophage Functions: Inflammatory Response and Phagocytosis

2019

Cells

181

119

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Autophagy is a conserved bulk degradation and recycling process that plays important roles in multiple biological functions, including inflammatory responses. As an important component of the innate immune system, macrophages are involved in defending cells from invading pathogens, clearing cellular debris, and regulating inflammatory responses. During the past two decades, accumulated evidence has revealed the intrinsic connection between autophagy and macrophage function. This review focuses on the role of autophagy, both as nonselective and selective forms, in the regulation of the inflammatory and phagocytotic functions of macrophages. Specifically, the roles of autophagy in pattern recognition, cytokine release, inflammasome activation, macrophage polarization, LC3-associated phagocytosis, and xenophagy are comprehensively reviewed. The roles of autophagy receptors in the macrophage function regulation are also summarized. Finally, the obstacles and remaining questions regarding the molecular regulation mechanisms, disease association, and therapeutic applications are discussed.

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“…Xenophagy is a specific type of autophagy that explains the process of delivering intracellular pathogens to the lysosomes via autophagic mechanisms [68]. It has been reported that the cellular cargo protein ubiquitin recognizes surface proteins of Mtb and activates the host xenophagy process to control intracellular growth of Mtb [69,70]. Primarily autophagy is regulated by the mammalian target of rapamycin (mTOR) complex 1 and the adenosine monophosphate-activated protein kinase (AMPK) [71,72].…”

Section: Autophagy and Tbmentioning

confidence: 99%

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

et al. 2020

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Tuberculosis (TB) is one of the leading causes of mortality and morbidity, particularly in developing countries, presenting a major threat to the public health. The currently recommended long term treatment regimen with multiple antibiotics is associated with poor patient compliance, which in turn, may contribute to the emergence of multi-drug resistant TB (MDR-TB). The low global treatment efficacy of MDR-TB has highlighted the necessity to develop novel treatment options. Host-directed therapy (HDT) together with current standard anti-TB treatments, has gained considerable interest, as HDT targets novel host immune mechanisms. These immune mechanisms would otherwise bypass the antibiotic bactericidal targets to kill Mycobacterium tuberculosis (Mtb), which may be mutated to cause antibiotic resistance. Additionally, host-directed therapies against TB have been shown to be associated with reduced lung pathology and improved disease outcome, most likely via the modulation of host immune responses. This review will provide an update of host-directed therapies and their mechanism(s) of action against Mycobacterium tuberculosis.

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A Mycobacterium tuberculosis surface protein recruits ubiquitin to trigger host xenophagy

Cited by 125 publications

References 69 publications

Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to controlMycobacterium tuberculosisinfection in macrophages

Galectin-8 senses phagosomal damage and recruits selective autophagy adapter TAX1BP1 to controlMycobacterium tuberculosisinfection in macrophages

Autophagy and Macrophage Functions: Inflammatory Response and Phagocytosis

Host-Directed Therapy as a Novel Treatment Strategy to Overcome Tuberculosis: Targeting Immune Modulation

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